Browsing by Subject "Ts65Dn mouse model"
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Item Correction of cerebellar movement related deficits by normalizing Dyrk1a copy number in the Ts65Dn mouse model for Down syndrome(Office of the Vice Chancellor for Research, 2016-04-08) Patel, Roshni; Stringer, Megan; Abeysekera, Irushi; Roper, Randall J.; Goodlett, Charles R.Elucidation of the underlying mechanisms involved in brain related deficits of Down syndrome (DS) would be useful for consideration of therapeutic interventions. Several DSspecific phenotypes have been hypothesized to be linked to altered expression or function of specific trisomic genes. One such gene of interest is D YRK1A , which has been implicated in behavioral functions of the hippocampus and cerebellum. The Ts65Dn mouse model for DS includes a triplication of D yrk1a in addition to a triplication of >100 other human chromosome 21 mouse orthologs. To evaluate the role of D yrk1a in cerebellar function, we have genetically normalized the D yrk1a copy number in otherwise trisomicTs65Dn mice and reduced D yrk1a copy number in otherwise euploid mice (2N) for a total of 3 alternative genetic doses of D yrk1a: EuploidDyrk1a +/+ , EuploidDyrk1a +/, Ts65DnDyrk1a +/+/+ , and Ts65DnDyrk1a +/+/. Cerebellar movementrelated function in these knockdown models is being assessed through a novel behavioral balance beam task. Additionally, levels of D yrk1a activity in the cerebellum for all genotypes were analyzed by HPLC. We have previously demonstrated that Ts65DnDyrk1a +/+/+ mice perform worse in the balance beam task in comparison to EuploidDyrk1a +/+ mice. Preliminary results of the current study do not indicate such a difference among Ts65DnDyrk1a +/+/+ mice in comparison to EuploidDyrk1a +/+ mice. We hypothesize that the lack of replication of the previous findings may be due to differences in postweaning housing environments. Mice in the previous study were singlehoused, whereas mice in the present study were grouphoused, which may help mitigate motor deficits in the trisomic mice. Additionally, current trends display a deficit in balance beam performance of both the EuploidDyrk1a +/and the Ts65DnDyrk1a +/+/groups, which suggests that reducing the copy number of D yrk1a by one may have detrimental effects on motor coordination. Concomitant analysis of the balance beam performances and Dyrk1a activity levels may indicate the sensitivity of the balance beam task to assess the role Dyrk1a activity in cerebellar function.Item Evaluation of the Effects of Green Tea Extracts on Bone Homeostasis in the Ts65Dn Down Syndrome Mouse Model(Office of the Vice Chancellor for Research, 2013-04-05) Abeysekera, Irushi S.; Thomas, Jared R.; Blazek, Joshua D.; Roper, Randall J.Down Syndrome (DS) is a genetic disorder that affects ~1 in 700 live births, caused by trisomy of human chromosome 21 (Hsa21), and results in cognitive impairment, craniofacial abnormalities, low muscle tone, and skeletal deficiencies. To study these phenotypes, we utilized the Ts65Dn mouse model, which contains three copies of approximately half the orthologous found on Hsa21 and exhibits similar phenotypes as found in humans with DS. Individuals with DS and Ts65Dn mice have deficits in bone mineral density (BMD), architecture, and bone strength. Over-expression of DYRK1A, a serine-threonine kinase encoded on Hsa21, has been linked to deficiencies in DS bone homeostasis. Epigallocatechin-3- gallate (EGCG), an aromatic polyphenol found in high concentrations in green tea, is a known inhibitor of Dyrk1a activity. Normalization of Dyrk1a activity by EGCG may have the potential to regulate bone homeostasis and increase BMD and bone strength in individuals with DS. In this study, we hypothesized that EGCG obtained from different sources would have differential effects in correcting bone deficits associated with DS. To test our hypothesis, we performed Liquid chromatography–mass spectrometry (LC-MS) on EGCG and related compounds from different sources. The LC-MS analysis determined the amount of EGCG and the degradation in our stock solution. Next, we treated three-weekold Ts65Dn and control male mice with EGCG for three weeks. At six weeks of age, mice were sacrificed. DXA and micro CT analysis were performed on the femurs and skulls of the mice to assess trabecular and cortical bone structure and BMD. Our results indicate the ability of EGCG to ameliorate skeletal deficiencies and compared pure EGCG with EGCG purchased from commercial vendors in correcting skeletal deficits associated with DS.Item TREATMENT OF CRANIOFACIAL DEFICITS ASSOCIATED WITH DOWN SYN-DROME IN A MOUSE MODEL(Office of the Vice Chancellor for Research, 2012-04-13) Chom, Alexis N.; Deitz, Samantha L.; Roper, Randall J.Trisomy 21 is the genetic source of the group of phenotypes commonly known as Down syndrome (DS). These phenotypes include cognitive im-pairment, heart defects and craniofacial abnormalities, including a small mandible. The Ts65Dn mouse model contains three copies of approximately half the genes found on human chromosome 21 and exhibits similar pheno-types to individuals with DS including a small, dysmorphic mandible. Our lab has traced this deficit to a smaller first branchial arch (BA1) consisting of fewer neural crest cells (NCCs) at embryonic day 9.5 (E9.5). At E9.5, Dyrk1a, a gene known to affect craniofacial development, is upregulated in the BA1, likely contributing to its cell deficit. Using epigallocatechin gallate (EGCG), an extract from green tea and a known inhibitor of Dyrk1a, we are attempting to rescue this deficit. We hypothesize the consumption of EGCG by pregnant mothers at E7 and E8 will rescue the mandibular deficit in de-veloping embryos by reducing the expression or activity of Dyrk1a. From our data we conclude the treatment of pregnant mothers with EGCG results in increased embryo size of trisomic embryos. Further analysis will be done to determine embryo volume, the volume of the BA1, and number of NCCs within the BA1 to determine the effects of EGCG in vivo. This research will better our understanding of craniofacial development and could lead to po-tential genetic-based therapies in the future.